WO2014191823A1 - Dérivés d'amines utilisables en tant qu'inhibiteurs de l'activité de l'il-15 - Google Patents

Dérivés d'amines utilisables en tant qu'inhibiteurs de l'activité de l'il-15 Download PDF

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Publication number
WO2014191823A1
WO2014191823A1 PCT/IB2014/000896 IB2014000896W WO2014191823A1 WO 2014191823 A1 WO2014191823 A1 WO 2014191823A1 IB 2014000896 W IB2014000896 W IB 2014000896W WO 2014191823 A1 WO2014191823 A1 WO 2014191823A1
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Prior art keywords
formula
amine derivatives
use according
compound
treatment
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PCT/IB2014/000896
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English (en)
Inventor
Katarzyna KOZIAK
Barbara ZYZYNSKA-GRANICA
Slawomir FILIPEK
Szymon NIEWIECZERZAL
Bartosz TRZASKOWSKI
Oliwia Zegrocka-Stendel
Malgorzata DUTKIEWICZ
Piotr Krzeczynski
Elzbieta KACZMAREK
Magdalena Winiarska
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Warszawski Uniwersytet Medyczny
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Publication of WO2014191823A1 publication Critical patent/WO2014191823A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the specific amine derivatives for use in the treatment of the diseases related to interleukin 15 overproduction.
  • Interleukin 15 is the cytokine exerting pleiotropic activity towards immune system cells as well as other cell types.
  • IL-15 exhibits broad spectrum bioactivity, therefore it is placed at the top of the pro-inflammatory cytokines cascade.
  • the impairment of the mechanisms regulating the expression of the IL-15 results in the overproduction of this cytokine and contributes directly to the development of such pathologies as inflammatory processes, autoimmune diseases, infections and neoplastic changes.
  • IL-15 is considered a crucial cytokine in the etiology of rheumatoid arthritis (Mclnnes I.B. et al., Nat. Med. 2, 175-82 (1996; Mclnnes I.B.
  • mice (Ruchatz H. et al., J Immunol. 160, 5664-60 (1998); Ferrari-Lacraz S. et al., J. Immunol. 173, 5818-26 (2004); Kim Y.S. et al., J. Immunol. 160, 5742-8 (1998)) and primates (Liew F.Y., Mclnnes I.B., Ann. Rheum. Dis. 61 Supl.
  • mice model of the disease Villadsen L.S. et al., J. Clin. Invest. 1 12, 1571-80 (2003)), reduction of carrageenan-induced inflammation in mice (Wei X et al., J. Immunol. 167, 277-82 (2001 )) and, also in mice, prolonged survival of heart allotransplants (Smith X.S. et al., J. Immunol. 165, 3444-50 (2000); Tinubu S.A. et al., J. Immunol. 153, 4330-8 (1994) and islets of Langerhans (Ferrari-Lacraz S.
  • RA Rheumatoid arthritis
  • Non-steroidal anti-inflammatory drugs are medications which as well as having pain-relieving (analgesic) effects have the effect of reducing the inflammation when used over a period of time. They suppresses the symptoms of the disease, but do not stop the progress of the illness.
  • DMARDs disease-modifying antirheumatic drugs
  • the other synthetic DMARDs are leflunomide, sulfasalazine, hydroxychloroquine, D-penicillamine, gold salts, azathioprine, cyclosporine and cyclophosphamide.
  • TNF tumor necrosis factor
  • infliximab chimeric anti-TNF monoclonal antibody
  • etanercept fusion protein, consisting of the extracellular receptor domain p75 for TNF and the Fc fragment of the human antibody lgG1;
  • adalimumab human anti-TNF monoclonal antibody
  • IL-1 receptor antagonist a ' nakinra (IL-1 receptor antagonist);
  • abatacept fusion protein composed of the Fc region of the immunoglobulin lgG1 fused to the extracellular domain of CTLA-4.
  • co-stimulating molecules B7-1 and B7-2 located on the antigen-presenting cells it inhibits the co-stimulatory signal transduction by CD28 on T cells;
  • - rituximab chimeric monoclonal antibody against the protein CD20 primary found on the surface of mature B cells acting by eliminating B cells.
  • Tocilizumab humanized monoclonal antibody against the interleukin-6 receptor, has been approved for the European pharmaceutical market as the first IL-6 inhibitor.
  • phase II clinical trials carried out by Amgen company with AMG-714 previously HuMax-IL15
  • HuMax-IL15 human monoclonal antibody that targets IL-15
  • Peptides of modified sequences mimicking IL-15 have been proposed as potential pharmaceuticals in the rheumatoid arthritis treatment. These peptides are supposed to bind to the receptor IL-15Ra subunit, which should result in the inhibition of the T cells proliferation, TNF-a induction and expression of IL-8 and IL-6. To date the efficacy of these new compounds has not been proved in clinical studies.
  • Phenylpyrazole anilide derivatives disclosed by Ushio H. et al. in Letters in Drug Design Discovery, 5, 292-296 (2008), are the only small chemical molecules of potential application in rheumatoid arthritis which interfere with the interaction of the receptor IL-15Ra and its ligand (IL-15).
  • the present invention relates to the discovery of a compound which will fulfill the criteria of Lipinski's rules for drug candidates.
  • the compound is expected to block the interaction between IL-15 and its specific IL-15Ra receptor by binding to the IL-15. Thus, it could be expect the compound will selectively and effectively inhibit the biological activity of this cytokine.
  • the present invention provides the compounds of the formula (I) or (II)
  • X represents C or N
  • Y represents CH 2 or NH
  • R 2 represents H lor COOH
  • the in vitro biological activity studies of the abovementioned compounds demonstrated the efficacious inhibition of the IL-15-induced cell proliferation and TNF-a and IL-17 expression by the amine derivatives of the formula (I) and (II).
  • the amine derivatives of the formula (I) or (II) could be used to inhibit IL-15 overproduction due to inhibition of IL-15 binding to its specific IL-15Ra receptor.
  • the compounds of the formula (I) or (II) can be used in prevention and therapeutic treatment of the diseases from the group including rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • the amine derivatives of the formula (I) or (II) can be used in treatment of rheumatoid arthritis.
  • the amine derivatives of the formula (I) or (II) according to the present invention can be administered to the individual in therapeutically effective doses to an individual in need of such a treatment, in particular to human.
  • Another embodiment of the present invention relates to the use of the compounds of the formula (I) or (II), their tautomers, isomers, pharmaceutically acceptable salts or solvates for manufacturing pharmaceutical preparations used in prevention or treatment of the diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • Next embodiment of the present invention relates to the pharmaceutical preparation consisting of therapeutically effective dose of the compound of the formula (I) or (II), or its tautomer, isomer, pharmaceutically acceptable salt or solvate as the active ingredient and pharmaceutically acceptable carriers and/or excipients.
  • Enamines of the formula (I) are susceptible to tautomerisation, forming appropriate imines or remaining in imine-enamine equilibrium. Different types of conjugations can occur, due to the presence of additional nitrogen atoms or carbonyl groups in the side chain of the molecule.
  • the compounds to be used according to the present invention are aminoimine derivatives of the formula (I),
  • Y represents NH
  • the compounds to be used according to the present invention are aminoimine derivatives of the formula (I), wherein:
  • Y represents CH 2
  • Ri represents CH 3 .
  • the compounds to be used according to the present invention are the substituted ⁇ -alanine derivatives of the formula (II),
  • R 2 represents H or CH 3 , and their optical isomers, in particular
  • the compounds according to the present invention exerting the highest biological activity are the derivatives of the formula (I), selected among 2,2'-imino-bis[(N-(aminoiminomethyl)acetamide] and 2,2'-((1E,3£)-1 ,3-dimethyl-1 ,3-propane-1 ,3-diylidene)-bis-carbaimidoylhydrazine as well as the derivatives of the formula (II) selected among ⁇ -alanyl-D-histidine and ⁇ -alanylhistamine.
  • the compounds of the formula (I) and (II) can be obtained and/or used as pharmaceutically acceptabled salts with acids.
  • the wording 'pharmaceutically acceptable salts' represents salts formed with pharmaceutically acceptable inorganic and organic acids. They can be selected from the group comprising, for example, hydrochloric acid, hydrobromic acid, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, adipic, ascorbic, salicylic, succinic, tartaric, acetic, citric, formic, benzoic, malic, p-toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic acid and others.
  • hydrochlorides are the salts of the derivatives of the formula (I) and (II).
  • the derivatives of the formula (I) or (II) can be used per se or in a combination with the other active ingredients at effective therapeutic doses, in treatment of the diseases or disorders, which have been diagnosed or they are likely to be related to IL-15 overproduction.
  • treatment refers to suppression of state, disorder or disease, that means inhibition, reduction or delay of the disease development, recurrence of the illness or at least one of its symptoms, or recovery, which means, regression of state, disorder or disease or at least one of its symptoms.
  • 'Therapeutically effective dose' refers to an amount of the compound, which is sufficient to produce therapeutic response when administered to the individual to cure state, disorder or disease.
  • 'Therapeutically effective dose' will vary, depending on the nature of the selected compound and a route of administration, kind of disease and its status, age, body weight, physical state, susceptibility to treatment and it can be recommended by the medical doctor on the basis of his own experience and results of the clinical trials.
  • Therapeutic dose of the derivatives of the formula (I) or (II) can be administered as a single dose or divided doses given in the certain intervals of time, for example as two, three, four or more daily doses.
  • pharmaceutical preparation except for active ingredient, may also contain known and pharmaceutically acceptable carriers and/or excipients, which are inert and do not interact with the active ingredient,.
  • composition may be formulated in any suitable pharmaceutical form for systemic administration, for example oral administration, such as tablets and capsules, starch capsules, coated tablets or enteral tablets; as powders or granules; as solution, suspension or emulsion.
  • Tablets and capsules for oral administration may contain excipients routinely used in pharmaceutical practice, such as binders, diluents, disintegrants or lubricants.
  • the tablets may be coated by any method known in the art.
  • Liquid pharmaceutical compositions for oral administration may be manufactured as, for example, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs or they may be produced as dry substances for preparation of solutions or suspensions ex tempore with water or other suitable diluent.
  • the liquid pharmaceutical preparations may contain, routinely used in pharmaceutical practice excipients, such as dispersing and emulsifying agents, non-aqueous carriers (they may comprise eatable oils) or preservatives. The selection and amount of the excipients depends on pharmaceutical dosage form and route of drug administration.
  • Pharmaceutical composition may be formulated into any suitable pharmaceutical form, by any method known in the art, using any pharmaceutically acceptable carriers, diluents, fillers and other excipients.
  • compositions for oral administration may be formulated, in particular, as capsules.
  • the active substance is combined with the carrier and the resulting composition is used to fill in the gelatin shells.
  • the gelatin capsules can be manufactured as having soft or hard gelatin shells, depending on the composition of gel mass used in a production process.
  • Soft capsules' gelatin mass consists of plasticizers, such as glycerol, sorbitol; preservatives, such as benzoic acid, its salts and alkyl hydroxybezoates; colorants and flavors.
  • the capsules' filling may be used as oily solution, suspension or emulsion.
  • the suitable diluents embrace, for example, castor oil, coconut oil, olive oil, palm oil, corn oil, arachis oil, synthetic and natural triglycerides of fatty acids, unsaturated medium-chain fatty acids, modified long-chain fatty acids, glycol esters, polyethylene glycols and others.
  • Suitable excipients comprise tensides, for example, lecitin, mono- and diglycerides, fatty acids esters with polyoxoethylene sorbitane.
  • composition suitable for parenteral administration may be used as ready suspension, lyophilizate, suspension ex tempore or concentrate for intravenous infusions.
  • These preparations may be formulated as unit dosage forms in ampoules, initially filled syringes, low capacity infusions, or in multi-dosage containers, consisting of preservatives and carriers, diluents, stabilizers and/or dispersing agents.
  • the carriers suitable for intravenous administration of pharmaceutical preparation comprise, for example, sterile aqueous solutions, such as the solution of physiological salt, the solutions of carbohydrates, for example, glucose, mannitol, dextrose, lactose and aqueous buffer solutions, for example, phosphate buffers.
  • the pharmaceutical composition may also contain other excipients, routinely used to maintain isoosmoticity, antioxidants, preservatives and the others.
  • the active ingredient may be used as a powder obtained due to isolation of the solid compound under septic conditions, or by lyophilisation from the solvent, for preparation of suspensions ex tempore in a suitable diluent, for example sterile, deprived of pyrogenic substances water.
  • the derivatives of the formula (I) and (II) have demonstrated biological activity in vitro studies.
  • these derivatives can be potential drug candidates used in protection and treatment of the diseases and inflammatory processes, which are related to IL-15 overproduction, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • Assay (Calbiochem, Merck, Germany). PBMC were seeded in a 96-well plate (25x10 3 cells in 200 ⁇ culture medium/well). Next day the cells were treated with the tested compounds at final concentrations: 20 ⁇ , 50 ⁇ , 100 ⁇ and 200 ⁇ . After 30 min. incubation with the compounds, the cells were stimulated with IL-15 at final concentration 5 ng/ml, incubated for 4 days, for last 24 h to the culture medium bromodeoxyuridine (BrdU) at concentration recommended by the manufacturer was added. After completion of the incubation the cells were centrifuged (10 min., 160xg) and fixed. Further experimental steps were performed according to the manufacturer's protocol.
  • the derivative L4 shows concentration dependent inhibition on interleukin 15-induced PBMC proliferation.
  • PBMC peripheral blood mononuclear cells
  • the tested compounds significantly inhibit IL-15-induced TNF-a synthesis in PBMC in comparison with the control cells stimulated with IL-15 alone.
  • PBMC peripheral blood mononuclear cells
  • All the tested compounds significantly reduce IL-15-induced IL-17 synthesis in PBMC in comparison with the control cells stimulated with IL-15 alone.
  • PBMC peripheral blood mononuclear cells
  • BrdU bromodeoxyuridine incorporation test
  • PBMC population consists of several cell types, these are lymphocytes and monocytes, which are characterized by the expression of IL-15 specific IL-15Ra receptor that explains their extensive proliferation in response to interleukin 15 stimulation.
  • Inhibition of cells proliferation in the presence of the tested compounds can be also the visible sign of cells death caused by cytotoxic or apoptotic activity of the analyzed derivatives. Effect of the selected benzoic acid derivatives on the cells viability was tested by two methods:
  • LDH lactate dehydrogenase
  • b Cytofluorometric assay with annexin V and propidin iodide for apoptosis and necrosis assessment.
  • Annexin V shows high affinity towards phosphatidilserine (PS), which is transferred to the outer leaflet of the plasma membrane in apoptosis.
  • PS phosphatidilserine
  • the appearance of PS on the cell surface is an indicator of initial or intermediate stage of cell apoptosis. Intact plasma membrane is not permeable for propidin iodide, but when the outer membrane loses its integrity, which occurs in necrosis, propidin iodide enters the cytosol and stains the necrotic cells.
  • PBMC Peripheral blood mononuclear cells
  • IL-15 stimulant to IL-15 stimulation not only by increased proliferation, but also synthesizing many pro-inflammatory cytokines, among others, for example, TNF-a and IL-17.
  • Inhibition of IL-15 biological activity should result in reduced proliferation and decreased synthesis of TNF-a and IL-17.
  • the selected derivatives at different concentrations were used to assess their Effect on IL- 5-related cytokine synthesis.
  • the biological activity of the compounds was evaluated measuring TNF-a and IL-17 concentrations in culture medium collected after incubation completion, using immunoenzymatic tests ELISA.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés d'acide benzoïque de formule I, comme décrit dans les revendications, leurs tautomères, leurs isomères, leurs sels pharmaceutiquement acceptables et leurs solvates, utilisables dans le cadre du traitement de maladies associées à la surproduction d'interleukine 15.
PCT/IB2014/000896 2013-05-31 2014-05-29 Dérivés d'amines utilisables en tant qu'inhibiteurs de l'activité de l'il-15 WO2014191823A1 (fr)

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PLP.404174 2013-05-31
PL404174A PL404174A1 (pl) 2013-05-31 2013-05-31 Zastosowanie pochodnych aminowych jako inhibitorów aktywności interleukiny 15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11278505B2 (en) 2017-04-24 2022-03-22 University Of Massachusetts Diagnosis and treatment of vitiligo

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WO1993004690A1 (fr) * 1991-09-09 1993-03-18 Peptide Technology Limited Procede de traitement de complications liees au diabete et de la pathologie du diabete
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WO1993004690A1 (fr) * 1991-09-09 1993-03-18 Peptide Technology Limited Procede de traitement de complications liees au diabete et de la pathologie du diabete
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